METTL14 Regulates Myocardial Infarction Progression via m6A-Dependent Modulation of OTUD1-Mediated Deubiquitination of DUSP6.

Myocardial infarction (MI) is the most severe clinical manifestation of coronary artery diseases (CVD) and serves as a critical driver of sudden cardiac death and heart failure (HF). Its pathophysiology begins with the abrupt cessation of coronary blood flow, leading to severe ischemia and subsequent cardiomyocyte necrosis. This study aimed to investigate the molecular mechanisms by which METTL14 regulates the progression of MI in mice via the OTUD1/DUSP6 signaling axis. An MI mouse model was established by ligating the left anterior descending (LAD) coronary artery. The progression of MI was evaluated through echocardiography, HE staining, Masson's trichrome staining, TUNEL assay, and assessment of inflammatory cytokines. Mechanistically, Me-RIP, PAR-CLIP Co-IP, and protein stability assays were performed to dissect the interactions within the METTL14/OTUD1/DUSP6 axis. Our results demonstrated that METTL14 was highly expressed in the MI mouse model. Silencing METTL14 significantly reduced the left Ventricular Internal Diameter at end-diastole (LVIDd) and left Ventricular Internal Diameter at end-systole (LVIDs), increased ejection fraction (EF) and fractional shortening (FS), and attenuated histopathological damage, apoptosis, and the levels of inflammatory cytokines (TNF-α and IL-β). Further analysis revealed that METTL14 promotes OTUD1 mRNA stability and expression by modulating its m6A modification. In turn, METTL14 influences DUSP6 expression by regulating OTUD1-mediated ubiquitination. Collectively, silencing METTL14 modulates the MI disease process through the OTUD1/DUSP6 signaling axis, suggesting that METTL14 plays a pivotal role in MI progression. These findings indicate that targeting METTL14 may represent a potential therapeutic strategy to alleviate pathological injury, apoptosis, and inflammation during MI.